An isoflavone-enriched diet alleviates Parkinsons disease in mice by inhibiting ferroptosis through gut microbiota-mediated serotonin production

Parkinsons disease is a severe neurodegenerative disorder whose pathogenesis is closely linked to gut microbiota dysregulation. However, whether and how modulation of gut homeostasis can ameliorate PD remains unclear.Dietary isoflavones have been associated with neuroprotective effects and show strong potential in shaping the composition of the gut microbiota, yet their underlying mechanisms in PD are poorly understood. Here, we show that an isoflavone-enriched diet alleviates motor deficits and dopaminergic neuron loss in an MPTP induced mouse model of PD. This protective effect is mediated via a gut brain axis mechanism. isoflavones promote the expansion of intestinal Lactobacillus species, especially Lactobacillus intestinalis, leading to increased 5_HT production in both serum and brain. Elevated 5-HT activates central 5_HT1A receptor, which in turn triggers downstream PI3K_AKT signaling to suppress ferroptosis, a key pathogenic process in PD. Pharmacological inhibition of either 5_HTR1A or the PI3K_AKT pathway abolishes the neuroprotective effects of 5_HT.Conclusions Our findings reveal a novel dietary-microbiota-serotonergic pathway that mitigates ferroptosis and neurodegeneration, highlighting the therapeutic potential of isoflavone-based interventions for PD.